2011 ASCO GIST Presentation Summaries

Nancy Berezin (left) and Becky Bensenhaver (right)

Nancy Berezin and Becky Bensenhaver (shown in the photo) attended the 2011 ASCO meeting on behalf of GIST Support International and reported on noteworthy presentations of importance for GIST patients. Their summaries, shown below, include links to the presentation abstracts at the ASCO website. Just click the listed abstract number to see the actual abstract
at the ASCO site.

ASCO will not make the virtual meeting (webcasts and slide shows) public on their website until 2014.

This phase 3 study was designed to compare the effects of one vs three years of adjuvant IM on both recurrence-free survival (RFS) and overall survival(OS) in high-risk patients, as well as evaluate the safety of three years of treatment. Bottom line: three years of IM delayed the time to recurrence and prolonged survival. Severe adverse events were infrequent. However, as Dr Blanke emphasized in comments that directly followed the presentation, three years is not a cure. As previously shown by the French investigators, interruption of IM therapy after one, three, or even five years in patients with advanced GIST is associated with rapid relapse -- although nearly all patients were able to achieve tumor control when IM was reintroduced. Might five to 10 years of therapy equal a cure? Dr Blanke didn't think so, given the likelihood that a small population of viable tumor cells would probably remain. (He added that more definitive information would be available when the results of the PERSIST-5 trial are published.) He also seriously questioned the feasibility of long-term IM therapy, pointing to the high rate of dropout in the three-year arm of the current study.

While severe adverse events were rare, Dr Blanke suggested that milder IM toxicities that might be acceptable over one year might not be bearable for many patients over the longer term. (Personal note: I am always amazed at what many physicians label as "mild." They should try living with it...) More research was needed, he said, to develop effective strategies to help patients tolerate long-term toxicities. Nevertheless, he said, the current study establishes three years of IM as the new "gold standard" for treatment of high-risk patients in the adjuvant setting. In fact, he personally plans to offer LIFETIME therapy to any patient who requests it, and will recommend it to all those whose risk of recurrence following surgery is 50% or greater.

Becky's comment: Hopefully, these new data will help provide the necessary scientific documentation preventing insurance companies from denying coverage for adjuvent gleevec for up to three years, if prescribed.

Molecular Translation: Bench to Bedside in Sarcomas

George D. Demetri, MD

Dr Demetri led off with a question: "What makes sarcomas -- which constitute only 1% of human cancers worldwide -- such a compelling set of diseases to target for research?" His answer was twofold: First, sarcomas are incurable by current therapies and thus represent "an important unmet medical need." Second, understanding the natural history of sarcomas offers insight into cancer pathogenesis in general, identifies signaling pathways for exploration, and provides a model for development of new, targeted therapies.

Dr Demetri then listed some of the barriers to sarcoma research. Because sarcomas affect such a small population, there is less incentive for drug makers to develop products to treat them. In addition, reliable results require large study populations, which are difficult to achieve when the disease is rare. Finally, because each sarcoma represents not one, but "potentially hundreds, if not thousands" of separate entities with different genetic profiles and clinical prognoses, they present a particular challenge when designing clinical trials. "The unpredictable heterogeneity of sarcomas, he said, can undermine the most rational and well-designed clinical trial."

If cancer has traditionally been regarded as a "black box," information from sarcoma research is prying open that box. For example, investigators now know that cell-signaling pathways are not simple and linear but involve multiple circuits and signal initiators. When one circuit is disabled, others quickly step in to take its place. We see this in GIST when a patient develops resistance to imatinib; KIT may have been knocked out by the drug, but other initiators such as RAS have stepped up their activity. The bottom line, said Dr Demetri, is that one cannot presuppose the mutational profile of any tumor. "You cannot assume that a mutation such as RAS is NOT present in a tumor, simply because its presence is rare." He added that DFCI will soon be offering GIST patients testing for a much broader array of genetic mutations than had been customary in the past. As new genomic and proteomic technologies become available, he said, it is important that patients take advantage of them, not just for the good of the patient but so that science can advance. Fortunately, he said, "patients today are very willing and able to partner with the professional community."

Prevalence of hereditary GIST susceptibility in adults with GIST.

Author(s): I. R. Rainville, E. J. Root, M. Salerno, L. DiGianni, D. A. Nelson, C. L. Corless, M. C. Heinrich, M. E. Robson, J. E. Garber; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Oregon Health & Science University, Portland, OR; Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR This was the 2011 update from Project FLAG, presented by lead investigator Irene Rainville, PhD. Background: Families with inherited mutations in KIT/PDGFRA have autosomal dominant transmission of GIST predisposition. Germline mutations of the tumor suppressor succinate dehydrogenase complex SDH) may underlie kindreds with GIST and paraganglioma, particularly in GISTS of the pediatric/wild-type histology. However, the prevalence of these is currently unknown. Project FLAG is an ongoing multicenter study to determine the prevalence of hereditary GIST in patients aged „18 years. Methods: Patients with confirmed GIST were recruited through sarcoma clinics at MSKCC and DFCI as well as a web recruitment tool. Participants were stratified to high- and low-hereditary risk groups based on questionnaire and family history review. Germline analysis of KIT and PDGFRA was conducted at OHSU on specimens from all high-risk subjects. Analysis of SDH is in process for a subset. Results: To date, 512 participants have been enrolled, and specimens from 92 high-risk and 41 low-risk subjects have been analyzed. Eight mutations were found in KIT, none in PDGFRA. Germline analysis of SDHx in five individuals with pediatric/wild-type GIST and/or family history of pheochromocytoma or paraganglioma is in progress. Conclusions: The hereditary form of GIST constitutes a small fraction of all GISTs. Individuals with GIST and without a family history of GIST in other relatives are unlikely to carry inherited susceptibility linked to the KIT or PDGFRA protooncogenes.

Who are the long responders to imatinib (IM) in patients with advanced GIST? Results of the BFR14 prospective French Sarcoma Group randomized phase III trial

This was a spinoff of the multicenter, Phase III BFR14 trial conducted by the French Sarcoma Group. Background: The goal of this analysis was to single out the subset of patients who derive the greatest benefit from imatinib (IM) in terms of prolonged response and overall survival. Methods: Of 434 patients enrolled in the BFR14 trial, 236 were selected. All patients had received IM 400 mg daily for at least five years. KIT and PDGFR mutations were analyzed using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of frequently mutated exons (KIT 9, 11, 13, 14, 18 and PDGFR 12, 14, 18), and the clinical and biological characteristics of patients with and without progression were compared. Results: As of January 2011, 197 patients had progressed or died since IM initiation, and 39 patients were free of progression. The characteristics of the long-term nonprogressors included a non-significant increase of gastric GIST, PS 0 (P=0.04), small tumor volume at inclusion (median 49 mm vs 102; p=0.003), absence of peritoneal disease, and exon 11 mutation that generally involved codons 557 and/or 558. Conclusions: Features associated with long-term response to IM included: good performance status, small tumor volume at study inclusion, and exon 11 mutation.

Correlation between imatinib trough levels and clinical benefit in gastrointestinal stromal tumors (GIST): Results of a prospective population pharmacokinetic study.

Data were given in a poster presentation (by Karel Eechoute) of a prospective study showing that there is an average decrease in Gleevec trough levels of 30% by the three month milestone after start of treatment. Following this 90-day decrease, a leveling off was observed. The number of patients participating in the study was not felt to be large enough to analyze the plasma concentration data by mutation type. Gleevec clearance was only marginally affected by the presence of liver metastases. In this study, it was determined that a mean minimum trough level concentrations (cMin) threshold of only 760 ng/ml was associated with a 65% reduction of time to progression (TTP) in advanced GIST, independent of localization and time to first recurrence. This is lower than the previous finding of a cMin of 1100 ng/ml for clinical benefit. It was suggested that Gleevec trough level testing should be time specific and may need to be repeated at 1 and also at 3 months after initiation of dosing.

The effect of crenolanib (CP-868596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors.

There appears to be promising news regarding the activity of a new oral drug, Crenolanib (CP-868596) in the treatment of D842V PDGFR-alpha metastatic mutant GIST. Crenolanib is being developed by AROG pharmaceuticals. It is presently in phase II trial at Fox Chase Cancer Center and Oregon Health Sciences University. Currently approved tyrosine kinase inhibitors (TKIs) such as gleevec or sutent have little or no activity against the D842V mutation. The results of this study describe Crenolanib as being effective in blocking activity of single or compound PDGFRa D842V mutant kinases, even in the case of PDGFRa V561D + D842V and PDGFRa T6741 + D842V. Phase I studies showed a favorable toxicity profile, and achievable serum concentrations as high as 2,000 nM. At this time, development of a Phase III placebo-arm trial for Crenolanib is being considered.

Dr. Suzanne George reported at ASCO on the results of a multicenter phase II study of Regorafenib in patients with metastatic GIST after failure of Gleevec and Sutent. What follows is a summary of Dr. George’s presentation. Regorafenib is a structurally distinct oral tyrosine kinase inhibitor with activity against several kinases including KIT, PDGFR, FGFR, VEGFR2 & 3, TIE-2, and BRAF. The trial goals were to evaluate the clinical benefit at the end point of at least 16 weeks. Tumor response was graded using RECIST criteria. Secondary trial objectives were to evaluate the safety and tolerability. 33 patients were enrolled and received the drug. A dose of 160 mg orally, 1x/day was administered on a cycle of 21 days on, 7 days off drug. Tumor assessments per RECIST were performed after 2 cycles. The most common side effects were hypertension, hand-foot skin reaction, and hyphophosphatemia (29%, 25%, and 14% of patients, respectively). Results: restaging scans performed on 22 patients who had been on the protocol at least 16 weeks showed sustained clinical benefit . 19 of 22 patients were without disease progression after 4 cycles of study drug dosing. Benefit was seen in patients whose tumors had primary KIT exon 11 mutations, KIT exon 9 mutations or wildtype kinase genotype. Immunoblotting of pre-study and day 15 matched biopsies demonstrated approx. 50% inhibition of KIT and AKT phosphorylation in 3 of 4 patients, all with stable disease for at least 4 cycles. Conclusions: Regoraenib has significant activity in patients with advanced GIST previously treated with Gleevec and Sutent. An international phase III trial is currently underway.

Dr. Jon Trent presented the results of a phase II study of dasatinib for patients with Gleevec-resistant and Sutent-resistant GIST . This presentation was given during a Sarcoma Oral Abstract session. Dasatinib is an oral tyrosine kinase inhibitor for KIT, PDGFR, ABL and SCR with a distinct binding affinity for KIT and PDGFR. Trial participants received 70 mg of dasatinib orally, twice a day. CT response rates were evaluated every 8 weeks by Choi criteria. The primary endpoint was a target progression-free survival at 6 months of at least 30%. Results: 50 patients were accrued (47 evaluable for response). The most common site of primary disease was stomach (59%) and metastasis was liver (56%). Primary median tumor size at diagnosis was 8.7 cm and mitotic rate was >5/50 hpf in 74% of patients. Tumor morphology was spindle (63%), epithelioid (18%) or mixed (18%). The median number of prior therapies was 2 (range 1-6), Gleevec (100%), Sutent (80%). Genotype was available for 15 patients: 6(40%) KIT exon 11, WT 2(13%), KIT exon 9(7%), and 1 (PDGFR D842V 1(7%). The median number of cycles was 2 (range of, 1-24). The partial response rate was 32% by Choi criteria. 21% of patients were progression-free > 6 months. Median progression-free survival and overall-survival were 2 months and 19 months. Median progression-free survival for patients with WT GIST was 8.4 months (range 1.2-27). Side effects included GI, respiratory, and myelosuppression. There were no deaths related to dasatinib. Conclusions: Dasatinib has significant activity by CT evaluation in Gleevec-resistant and Sutent-resistant GIST but did not meet the predefined 6 month progression-free survival rate of 30%. Mutational and molecular analysis of the data is pending.

From time to time there are questions from the list pertaining to KIT-negative GIST. The Spanish Group for Sarcoma Research (GEIS) presented a poster at ASCO on this topic, which I will summarize below. There are scarce and controversial findings published on KIT-negative GIST-like (KNGL) tumors. One of the largest studies analyzing KNGL found two distinct subsets according to immunostaining: DOG1+ cases were gastric with PDGFRA mutations and DOG1- cases were gastric or intestinal both alike. In the present study, analysis of expression of genes known to be implicated in GIST as well as miRNA221/222 (negative regulators of KIT) was performed. They also analyzed for KIT and PDGFRA mutations, DOG1 immunostaining and clinical outcome. Analyses obtained from gene expression data identified two distinct groups: Group I: Had an overexpression of KIT, DOG1 and PDGFRA, and underexpression of IGF-1R; with predominance of epithelioid gastric cases, DOG1+ immunostaining and PDGFRA mutations. On the contrary, Group II had overexpression of IGF-1R and underexpression of KIT, DOG1 and PDGFRA; most cases were non-gastric with DOG1- immunostaining and KIT mutated or wild type. . Group II had a significantly worse prognosis for both metastasis free and overall survival. The expression of miRNAs was lower in a subset of cKIT+ cases compared with this KNGL series for miRNA221 and for miRNA 222. Interestingly, the overall survival was significantly worse in cases with higher expression of miRNA221 or miRNA222 in KNGL Conslusions: The results identify the existence of two distinct subsets of KIT-negative GIST-like cases also at the gene expression level with a different prognostic value. Increased levels of miRNA-221/222 could explain the absence of protein expression of most such cases. Finally, the fact of worse survival associated to higher miRNA 221/222 expression level deserves further investigation.

In regard to Wildtype (WT) GIST: Dr. Maria Pantaleo presented poster results from an Italian group of researchers. They analyzed the tumors of two young adults with sporadic WT GIST using massively parallel sequencing in order to identify previously unidentified genetic mutations. Although the presence of SDHB and SDHC mutations have been previously reported in WT GIST patients, this is the first study that identifies mutations in SDHA. This finding was expanded to a slightly larger cohort of WT GIST patients, with SDHA mutations being identified in 4 out of 10 patients analyzed. They felt that this gene should be evaluated in larger series and be added in the sequencing screening of WT GISTS.

The same group of Italian researchers presented data pertaining to WT GIST in a different poster. They analyzed the miRNA profile of 13 GIST tumor samples, 9 with KIT or PDGFRA mutations and 4 WT (without KIT or PDGFRA mutations). Results: The miRNA profile is different in WT vs. mutated GIST samples, with 56 miRNAs differentially expressed. The miRNAs hsa-let-7b and has-let-7c, that target IGF-1R are the most significantly differentially expressed. They felt that these miRNA differences warrant further investigation in order to understand their potential role as a causative factor in WT GIST and treatment responsiveness.

Nancy spoke with Dr. Van den Abeele during one of the poster presentation sessions. Dr. Van den Abeele stated that what was very important in regard to the regorafenib findings was the significant change of the metabolic response early (from the first dose) on PET scan analysis. Responses were consistent over the course of the study (cycle 1 relatively the same as cycle 4) per PET. She stated that there seems to be a synergistic metabolic response with the drug metabolites as well as the parent compound. So, they may be able to get more out of each dose or space doses more widely. Between cycles is washout; she hypothesized that perhaps the metabolites carried over some control into the washout period.

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